Topic angiotonic compositions



1965 P. M. CURTAY ETAL 3,200,037

TOPIC ANGIOTONIC COMPOSITIONS Filed Jan. 22. 1962 United States Patent3,200,037 7 TOPIC ANGIIOTONIC CGMPOSITIONS Paul M. Curtay and AdrienneM. Curtay, born Boelens, both of 116 Blvd. Perch-e, Paris, France FiledJan. 22, 1962, Ser. No. 167,659 Claims priority, application France,Feb. 10, 1961, 852,248; Sept. 30, 1961, 874,664

2 Claims. (Cl. 167-62) It is an object of this invention to providepharmaceu tical compositions to be applied locally on skin for thetreatment of circulatory disorders, more particularly pharmaceuticalcompositions to be maintained locally on the skin of an upper or lowerlimb with a view to improving in depth circulatory insufliciency, moreespecially predominantly venous or venolymphatic circulatoryinsufiiciency.

Another object is to provide compositions as aforesaid useful forprophylactic, therapeutic or cosmetic purposes.

Up to this time, from a prophylactic standpoint uneasily applicable orlittle efficient precepts had been given. Creams to be applied byrubbing have the inconvenience of congesting tissues which on thecontrary should be decongested. Special Nylon stockings as proposedoften produce an unpleasant heat feeling. True varix stockings provide adesirable aid, but few women accept to wear the same at an age at whichprotection is still possible. Cures in watering places are often toocostly, considering the sojourn expenses and the loss of salary forthree weeks.

From a therapeutic standpoint sclerose and surgery do away with the badparts,they improve circulatory hydraulics, but there is no improvementin depth of tissues and vessels. Furthermore there are numerous cases inwhich both methods cannot be resorted to either by reason of a lack ofvisible veins to be removed, or because people are scared of injectionsor surgery, or because any one of those methods previously appliedfailed to produce the expected result.

Our method and compositions have been devised more particularly for thefollowing curative, prophylactic and esthetic purposes:

(1) Curative purposes: treatment of disorders arising from the presenceof more or less important varices, ulcers, recent or old phlebitissclerous, hypodermites (lymphlegs); associated troubles such as edemas,varicose eczema and stiffness in joints, and lymphedemas in upper andlower limbs (in the latter case as a complementary treatment associatedwith intermittent compression treatment).

(2) Prophylactic purposes: patients about to be operated or as a pre-,peror post-operatory treatment in the case of admittedly thrombogenousoperations, for pregnant women or after delivery, for patients havingfamilial varicose records, for standing workers (e.g. shopmen and women,dental surgeons, mothers of family), for preventing lymphangitis rashes,for persons having varicosities.

(3) Esthetic purposes: cases of cellulitis, thinning of legs and ankles,heaviness feeling, tiredness in the evening or during hot periods,swelling Without apparent medical reason in the evening or during hotperiods, red or purplish colour, feeling of burning or cold in feet.

We have found that for preventively or curatively treating circulatorydisorders, particularly in legs, both for therapeutic and estheticpurposes, it is desirable to provide ibfifid? Patented Aug. 10, 1%65compositions to be laid without rubbing and maintained on skin, andwhich are so compounded as to comprise along with an angiotonic agent oragents capable of being absorbed transcutaneously, one or more volatileagents effective to cause a mild cooling of skin and underlying tissues,i.e. a mild hypothermia (hibernotherapy).

The maintenance of such a composition on a more or less wide area ofhuman body skin, for example a leg or portion of a leg, may bevisualized as a local bathing, the effects of which may be compared tothose of a cure in a health resort but are more quickly and intensivelydeveloped.

Angiotonic agents of vegetable origin of the class of benzoin tinctureand preparations containing vitamin P were found particularly effectivefor association with a volatile cooling agent or agents; for practicalpurposes we found by research and experiment that liquid extracts ofhamamelis and benzoin extracts should be preferred although otherpreparations containing vitamin P such as horse-chestnut extracts andalcoholatures, and compositions containing rutoside may also beemployed.

Suitable volatile cooling agents which may be employed singly or jointlyare acetone, camphor, menthol, ethyl .ether and chloroform. Preferablecooling agents are camphor and menthol which appear to produce afavorable angiotonic effect in addition to produce a mild hypothermia.It is well-known that applied on skin camphor and menthol determine afeeling of coolness. For example camphor which volatilizes at 15 C.causes a mild hypothermia if it is contacted with leg epidermis at atemperature of 28 C.

A further desirable ingredient of our compositions is ethyl alcoholwhich plays the roles of a carrier, of a penetrating agent, assistingthe ingress of the angiotonic agent or agents into and through theepidermis and derm, and also of a cooling agent. Alcohol is capable ofdissolving fats and also produces a vasodilation facilitatingpenetration before cold has produced a vasoconstriction, the sequence ofwhich is believed favorable as vasomotricity gymnastics.

A still further desirable ingredient of our compositions is glycerolwhich is useful as a carrier for the angiotonic and cooling agents. Itis our feeling as a result of numerous experiments that glycerol has afavorable effect which is not simply that of a carrier, in the treatmentof the disorders above referred to, but so far we are not in position tobring a scientifically satisfactory proof of that effect. An alternativecarrier for liquid compositions is propylene glycol.

Menthol 2.5 to 6% Camphor 2 to 4% Ethyl alcohol percent by volume) 20 to30% "Chloroform 2 t0 6% Benzoin tincture 2 to 5% Hamamelis liquidextract 10 to 15% Glycerol (30 B.) 61.5 to 34% The hamamelis liquidextract referred to (Extractum Hamamelidis liquidum) is produced bypercolating moderately coarse hamamelis leaf with 45 percent ethylalcohol, and the benzoin tincture (Tinctura benzoinis) by causingcrushed benzoin (200 g.) to macerate for days in 75 percent ethylalcohol then filtering.

A particularly effective composition (A) contains the above ingredientsin the following proportions by weight:

In making composition (A), it is preferred to add crystalline camphor tomenthol, to leave the mixture standing for say 24-48 hours, to addchloroform, then alcohol and afterwards benzoin tincture and hamamelisliquid extract while stirring, and to leave the mother mixture or masterbatch thus prepared standing for say 24 hours or more. Glycerol may beadded at the time or later, the composition being stirred at the time ofuse.

In the above compositions when used for cosmetic purposes, chloroformmay be omitted, the ethyl alcohol and/or glycerol being increasedcorrespondingly. To the angiotonic agents shown as being hamamelisliquid extract and benzoin tincture may further be added azulene,alantoin or histamin by as small an amount as about 0.001 to about 0.1%;azulene and/ or histamin are desirable for patients liable to eczema.Also a perfume may be added.

Further compositions also found to be effective particularly forcosmetic purposes are given below to illustrate possible modificationsin the nature and proportions of the ingredients.

7 Percent Camphor 4.7 Ethyl alcohol (90 percent by volume) 17 Benzointincture 1.7

Azulene 0.3 Perfume 0.3 Glycerol 26 Distilled water 50 Percent Ethylalcohol (90% by volume) 12 Menthol 2.25 Hamamelis liquid extract 6.75Propylene glycol or glycerol 79 then one to three like bands may .bewound similarly, and

the combination is coveredwith a dry band for example a cotton band. JSuch a bandage will be renewed as frequently as required, generallytwice or three times a week;

' In average cases, twelve bandage applications are enough;

more are required in the case of a severe ulcer, phlebitisorpost-phlebitis disorders. The treatment is an ambulatory treatment, norest being required. i

With less severe cases, a.thicker,-'slightly elastic band, preservingits resiliency after impregnation with the pharmaceutical compositionmaybe applied, such a band being wound preferably from the toes to thetop of the thigh with a view to compensating for the shorter period ofapplication one hour for example, by means of a wider application area.

With still milder cases or for estheticpurposes where the patient wishesto be treated at home or by himself or herself, it is desirable toemploy a sheath or hose which will now be described (reference Will alsobe made to copending US. patent application Serial No. 109,522 filed May12, 1961 in the name of Adrienne M. Curtay).

The sheath is made of an absorbing, resilient material adapted to beimpregnated with the pharmaceutical composition; said sheath may havethe shape of a complete hose, a sock, with or without toe end, or athigh piece, to be placed on the leg or corresponding 'part of leg andretained thereon by its own elasticity; it may be made of woven orknitted fabric with or without ribs, resiliency being provided by thetexture and/or the nature of the material, and/or by incorporatingresilient, for example rubber threads in the fabric.

Although cotton is preferred as'a constituting material for the sheath,other materials, whether textile or not, may be employed.

Such a sheath after it has been impregnated with the pharmaceuticalcomposition and put on the leg is adapted to maintain a considerableamount of the active components of the composition in contact with theleg skin providing a kind of permanent bathing in the pharmaceuticalcomposition.

The absorbing sheath may be combined with an impervious sheath havingthe same shape which may be made of any impervious, flexible material tobe placed over the absorbing sheath. 'The impervious sheath is madepreferably of a plastic material, in particular from a polyvinylchloride or other thermoplastic material sheet which is' cut to thesuitable shape and welded, or of impervious textile material suitablysewn or Welded. The imperviousisheath is effective to prevent the garments from being moistened or stained by the pharmaceutical composition.

The impervious sheath is preferably made with suitable resiliency to bemaintained in positionon the absorbing sheath or as the case may be tomaintain the absorbing sheath in position on the limb. For that purpose,the irnpervious sheath may have ribbed edges or may be provided withseparate resilient edgings, or arranged to be held with garters. 7 a

Alternatively the absorbing sheath and the impervious sheathmay becombined into a piece of garment, the absorbing sheath providing aninner lining for the impervious sheath. For practical purposes, thepiece of garment is turned inside out to expose the absorbing facethereof which is impregnated with the pharmaceutical composition thenthe Whole is turnedagain and the leg introduced into the same.-

In the herewith drawings, illustrating our invention:

FIG. 1 shows an absorbing sheath, i

FIG. 2 shows an impervious sheath,

FIG. 3 shows the absorbing sheath only partly covered with theimpervious sheath.

FIG. 4 is an exploded view of the top portion of an absorbing sheath andan impervious sheath placed .over the same. 4 p

For thetreatment of a leg 1, an absorbing sheath 2 (FIG. 1), preferablymade of cotton and adapted to be impregnated with a pharmaceuticalcomposition is shaped as a hose to be placed as shown on FIG. 3. I V

An impervious sheath 3 (FIG. 2) made of plastic'material or rubbe'redtextile fabric for example, is adapted to be placed over the absorbingsheath 2 and has the.

same hose shape; the impervious sheath 3 may be formed with a top,resilient, ribbed squeezing section 4 as shown or alternatively may beemployed with garter. The impervious sheath 3 is shown on FIG. 3 beforeit has been completely drawn over the absorbing sheath 2.

It will be readily apparent that like sheaths may be made to be placedon an arm.

Instead of impregnating a porous support with the pharmaceuticalcomposition and placing the support on skin as described, it is possibleto spray the composition, provided the composition is fluid enough, bymeans of an inert gaseous propellant such as nitrogen or a Freon eitherdirectly on the skin or on and through a porous support previously laidon skin. The composition may be compounded to contain a propellant asemployed for aerosols which is liquid under the pressure prevailing inthe container provided with a spray nozzle.

In the development of our invention, the first step in our research wasthe local application of CO snow. We were impressed in finding that athickened face skin (trophic disorders) with dilated vessels(circulatory disorders) gave a very favorable response to slight, simplyweekly applications of carbonic snow.

We then attempted to act similarly on trophic and circulatory disordersin lower limbs. As physical agents such as carbonic snow did not proveto be satisfactory enough, we substituted therefor one then several ofthe above mentioned volatile cooling agents. We then conceived to addangiotonic agents as above set forth. The best results were obtainedwith a temperature drop of from about 2 to about 5 C. The desired dropin the various cases was induced with a single or several volatilecooling agents according to the rate of volatilization. It was foundthat a mild hypothermia causes the local metabolism to be lowered,inhibiting catabolism more than anabolism. In spite of the oxygenscarcity due to stasis, diseased tissues were eventually regenerated andshowed transformations which characterize young tissues.

With the addition of angiotonic medicines to said cooling agents, wefound -a therapeutic and prophylactic effect showing a synergeticcooperation, which is by far more potent than the effects of thecomponents considered singly. There is a surprising therapeutic effectwhich is proved clinically and corresponds to a restoredto-normal,functional condition with almost complete disappearance of some lesions.Although our invention should not be considered as limited by anytheoretical tentative explanation, the effect obtained is likely to beascribable to hypothermia placing tissues in a relative rest conditionby lowering the metabolism thereof and rendering said tissues morereceptive to the action of angiotonic agents by a potentializatingeffect.

Ulcers quickly heal and the tissues which are rebuilt do not have thecigarette paper thinness found after application of usual medicalmethods, nor a pigmented or blackish color, but have the color ofhealthy tissues and an absolutely normal consistence. Any admittedlyirreversible lesions such as pigmentations of old ulcers or darkpigmentary dermititis of varicose patients, with or without sclerosisare more clear and flexible in most cases. Pain is alleviated thendisappears very quickly pari passu with a recovery of normal functionalcondition in about 90 percent of cases, whether benign or severe. Recentphlebitis can be healed by means of our pharmaceutical compositionswithout anticoagulating agents and without requirement for rest:post-phlebitic disorders such as edemas, pains, joint stiffness,indurated hypodermitis and various troubles with chronic varicosepatents are improved to a wide extent. Our pharmaceutical compositionscause disappearance of the feeling of heaviness, tiredness and pains ofstanding workers and pregnant women; they also provide a usefulassistance in the treatment of upper limb circulatory disorders, inparticular lymphedemas following mastectomy, painful or painlesslymphedemas of lower limbs, lymphangitis and cellulitis (in the lattercase the improvement in blood circulation renders the tissues receptiveto action of conventional treatments which have been so farineffective), pre-, perand post-operation prevention in admittedlythrombogenous surgical operations or with predisposed varicose patients.The compositions of this invention enable of preparing patients forsclerosis or surgery or varicose veins because they improve bloodcirculation in depth and impart increased vitality to tissues andvessels.

Our pharmaceutical compositions are also of prophylactic interests forthose who have familial varicose records or are predisposed by reason oftheir calling or a pregnancy condition, or for those who have smalllesions such as varicosities, slight edema in the evening or like signsindicating a latent venous or venolymphatic insufiiciency. Thecompositions according to this invention produce a quick lightening oflegs, a removal of the permanent feeling of burn or cold, a steadythinning and a more natural color, which should be appreciated by womenwho take care of the esthetic appearance of their legs.

What we claim is:

1. A composition for improving in depth predominantly venous orvenoylmphatic circulatory troubles in limbs, which comprises from 2.5 to6 percent by weight of menthol, 2 to 4 percent by Weight of camphor, 20to 30 percent by weight of percent by volume ethyl alcohol, 2 to 6percent by weight of chloroform, 2 to 5 percent by weight of benzointincture, 10 to 15 percent by weight of hamamelis liquid extract and61.5 to 34 percent by weight of glycerol.

2. A composition for improving in depth predominantly venous orvenolymphatic circulatory troubles in limbs, which comprises 4 percentby weight of menthol, 2.5 percent by weight of camphor, 23.5 percent byweight of 90 percent by volume ethyl alcohol, 4 percent by weight ofchloroform, 3 percent by weight of benzoin tincture, 13 percent byweight of hamamelis liquid extract, and 50 percent by weight ofglycerol.

References Cited by the Examiner UNITED STATES PATENTS 74,622 2/ 68Smith 167-62 95,771 10/ 69' Conroy 167-62 1,427,199 8/22 Foote 167-62OTHER REFERENCES Current Therapy, 1960, published by W. B. Saunders Co.,Philadelphia, page 167.

Kloss: Back to Eden, published by Longview Publishing House, Coalmont,Tennessee, 1958, pages 212, 213, 330, 369.

Redgrove: The Industrial Chemist, pages 219-220, May 1936.

United States Dispensatory, 24th edition, published by J. B. Lippi'ncottCo., Philadelphia, pages 34, 147, 208, 209, 26 7, 670, and 1730.

Vitamins and Hormones, vol. 7, published by Academic Press Inc., NewYork, 1949, pages 12, 13, 48, and 49.

JULIAN S. LEVITT, Primary Examiner.

FRANK CACCIAPAGLIA, LEWIS GOTTS, Examiners.

1. A COMPOSITION FOR IMPROVING IN DEPTH PREDOMINANTLY VENOUS ORVENOLYMPHATIC CIRCULATORY TROUBLES IN LIMBS, WHICH COMPRISES FROM 2.5 TO6 PERCENT BY WEIGHT OF MENTHOL, 2 TO 4 PERCENT BY WEIGHT OF CAMPHO, 20TO 30 PERCENT BY WEIGHT OF 90 PERCENT BY VOLUME ETHYL ALCOHOL, 2 TO 6PERCENT BY WEIGHT OF CHLOROFORM, 2 TO 5 PERCENT BY WEIGHT OF BENZOINTINCTURE, 10 TO 15 PERCENT BY WEIGHT OF HAMAMELIS LIQUID EXTRACT AND61.5 TO 34 PERCENT BY WEIGHT OF GLYCEROL.